Biological Signatures, Probiotic Among Those With mTBI and PTSD

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Exaggerated inflammation in the body and brain is thought to play a role in the vulnerability to and aggravation and perpetuation of adverse consequences among those with co-occurring mild TBI (mTBI) and post-traumatic stress disorder (PTSD). The proposed study begins the process of investigating the use of a natural immunoregulatory/anti-inflammatory probiotic to treat chronic symptoms associated with co-occurring mTBI and PTSD among Veterans. By looking at the impact of probiotic supplementation on biological signatures of increased inflammation, as reflected by the gut microbiota, gut permeability, and biomarkers of peripheral inflammation, this study may lead to the identification of a novel intervention for the treatment of symptoms associated with these frequently co-occurring conditions.

United States military Veterans from recent conflicts are coping with symptoms related to mild traumatic brain injury (mTBI), persistent post concussive (PPC) symptoms, and posttraumatic stress disorder (PTSD). Many Veterans are resistant to conventional health and mental health interventions (e.g., medication, psychotherapy), and often symptoms are not significantly improved by traditional treatments. Moreover, there are limited treatments for symptoms associated with both conditions, which frequently co-occur. Alternative treatment methods are needed. One potential common underlying feature of both mTBI and PTSD is exaggerated inflammation, both peripherally and in the central nervous system, which is thought to play an important role in the vulnerability to, aggravation of, and perpetuation of adverse consequences of these often co-occurring conditions. Therefore, a novel intervention strategy would be the use of immunoregulatory/anti-inflammatory probiotics to reduce inflammation. In this study, the investigators will investigate the effects of an immunoregulatory probiotic on both biological signatures of systemic inflammatory processes and proximal signatures of probiotic administration. Lactobacillus reuteri (L. reuteri), a commensal organism that colonizes the human gut mucosa, suppresses mucosal inflammation via inhibition of the production of proinflammatory cytokines, and is the probiotic of interest. Specific aims of the study are to determine the: 1) effects of L. reuteri on biological signatures of gut microbiota, gut permeability, systemic inflammation processes, and stress responses; 2) feasibility of L. reuteri supplementation; 3) acceptability of L. reuteri supplementation; and 4) tolerability and safety of L. reuteri supplementation. Project aims will be assessed using a longitudinal, double blind, randomized placebo-controlled design. Participants will be Veterans with PPC symptoms, PTSD, and evidence of elevated systemic inflammation (based on high baseline plasma C-reactive protein [CRP] concentrations). After initial evaluation procedures, 20 participants will be randomized to probiotic supplementation and 20 will be randomized to placebo supplementation. The proposed line of research addresses the Office of Rehabilitation Research and Development (RR&D) Service's goal of identifying means of intervening to increase function among those with mTBI and co-occurring psychiatric conditions. Long-term, this study may lead to a paradigm shift in the manner by which the investigators target clinical symptoms associated with PPC and PTSD symptoms, by beginning the process of supporting a multitargeted, neuroprotective approach.

Commercially available L. reuteri (deposited in the Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ) and referenced as DSM 17938; Gerber Soothe Colic Drops, 100 million CFU/5 drops; formerly known as L. reuteri ATCC 55730) will be used in the proposed study. L. reuteri (phylum Firmicutes) is a gram-positive anaerobic commensal bacteria found in the gut microbiome of humans. Independent testing of the viability of the commercial product will be conducted in our laboratories by diluting drops, plating on agar in triplicate, and anaerobic culturing at 37 oC. The commercial strain (DSM 17938) has been used to improve intestinal functions in infants and reduce symptoms of infantile colic.

Dietary Supplement: of Lactobacillus reuteri (L. reuteri; DSM 17938)

Commercially available L. reuteri (deposited in the Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ) and referenced as DSM 17938; Gerber Soothe Colic Drops, 100 million CFU/5 drops; formerly known as L. reuteri ATCC 55730) will be used in the proposed study. L. reuteri (phylum Firmicutes) is a gram-positive anaerobic commensal bacteria found in the gut microbiome of humans. Independent testing of the viability of the commercial product will be conducted in our laboratories by diluting drops, plating on agar in triplicate, and anaerobic culturing at 37 oC. The commercial strain (DSM 17938) has been used to improve intestinal functions in infants and reduce symptoms of infantile colic.

C-Reactive Protein [ Time Frame: Through study completion, an average of 8 weeks ]

Inflammation - Biological Signature (Blood) - The investigators will use high sensitivity ELISA assays, conducted in duplicate wells, from R&D Systems to measure a biological signature of exaggerated inflammation.

Secondary Outcome Measures :

Tumor Necrosis Facto [ Time Frame: Through study completion, an average of 8 weeks ]

Inflammation - Biological Signature (Blood) - The investigators will use high sensitivity ELISA assays, conducted in duplicate wells, from R&D Systems to measure a biological signature of exaggerated inflammation.

Other Outcome Measures:

Interleukin 6 [ Time Frame: Through study completion, an average of 8 weeks ]

Inflammation - Biological Signature (Blood) - The investigators will use high sensitivity ELISA assays, conducted in duplicate wells, from R&D Systems to measure a biological signature of exaggerated inflammation.

Gut Microbiome (Stool) [ Time Frame: Through study completion, an average of 8 weeks ]

Biological Signature - Stool - Microbial DNA will be prepared with a QIAGEN high-throughput system (QIAsymphony SP) capable of handling 96 samples simultaneously. Microbes will be eluted from one of the two stool swabs in each tube (the second stored frozen as a contingency) and DNA prepared using the QIAGEN system.

qPCR quantification of 16S rDNA in plasma [ Time Frame: Through study completion, an average of 8 weeks ]

Inflammation - Biological Signature (Blood) - The investigators will use high sensitivity ELISA assays, conducted in duplicate wells, from R&D Systems to measure a biological signature of exaggerated inflammation.

Heart Rate Variability [ Time Frame: Through study completion, an average of 8 weeks ]

Stress Response - Centrally placed remote heart rate monitor around the base of the sternum will be used to collect this data

Galvanic Skin Response [ Time Frame: Through study completion, an average of 8 weeks ]

Stress Response - will be with distal phalanges of the first and second fingers of the non-dominant hand.

Visual Analog Scale [ Time Frame: Through study completion, an average of 8 weeks ]

Stress Response

Psychological Stress Measure-9 [ Time Frame: Through study completion, an average of 8 weeks ]

Stress Response - 9 item self report measure

Adverse Events [ Time Frame: Through study, an average of 2 years ]

Number of Adverse Events reported to IRB

Generic Assessment of Side Effects - Probiotics (GASE-P) [ Time Frame: Through study completion, an average of 8 weeks ]

Tolerability - Consists of 36 symptom descriptions organized by body parts. Participants are asked to rate if these "symptoms" were either "not present", "mild", "moderate", or "severe" in the past week related to supplementation

Adult AIDS Clinical Trials Group (AACTG) [ Time Frame: Through study completion, an average of 8 weeks ]

Feasibility - Adult AIDS Clinical Trials Group (AACTG). We will use only section G of this measure, which queries why one might not take a supplement as directed

Feasibility - The MMAS is designed to test whether or not a subject adheres to taking a particular medication or supplement, and has demonstrated concurrent and predictive validity in regard to the measurement of patient adherence in clinical studies.

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Layout table for eligibility information

Ages Eligible for Study:

18 Years to 50 Years (Adult)

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

History of at least one deployment in support of Operation Enduring Freedom (OEF)/Operation Iraqi Freedom (OIF)/Operation New Dawn (OND)

History of mTBI per the Ohio State University (OSU) TBI-ID85 with any endorsement of post concussive symptoms (PCS) associated with an mTBI, which occurred at least 6 months prior to the baseline assessment

Current symptoms in 3 or more of the following ICD-10 Post Concussive Symptom86 categories as measured by the Rivermead Post Concussive Symptom Questionnaire (RPCSQ87; score of 2 or greater per symptom to qualify):

headache

dizziness

malaise

fatigue

noise intolerance

irritability

depression

anxiety

emotional lability

subjective concentration

memory

intellectual difficulties

and/or insomnia

Current diagnosis of PTSD per the Clinician Administered PTSD Scale-5 (CAPS-5)88

Medical clearance by study physicians to participate in the protocol

Age between 18 and 50

Ability to provide informed consent

Willingness not to take probiotic supplements (pills, tablets, oils, etc.) other than the product provided in the clinical study until all study procedures are completed

Currently involved in the criminal justice system as a prisoner or ward of the state

Non-English speaking

Current (past month) alcohol or substance abuse or dependence

Lifetime history of bipolar disorder or psychosis or anxiety disorders (excluding PTSD)

Current major depressive disorder (MDD)

Consistent (e.g., 5x/week or greater) probiotic supplementation within the last month, including probiotic food products such as yogurt, as determined by phone screen interview and Probiotic Food Check List

Receiving antibiotics within the last month; use of topical antibiotics or topical steroids on the face, scalp, or neck or on arms, forearms, or hands within the previous 7 days